Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use

Abstract

Novel anti-estrogenic compounds are provided which are useful to treat a variety of disorders, particularly estrogen-dependent disorders. Preferred compounds have a 1,3,5-estratriene nucleus, and are substituted at the C-17 or C-11 position with a molecular moiety which renders the compounds effective to competitively block the binding of estrogen to its receptor. Particularly preferred compounds are 17-desoxy-1,3,5-estratrienes. Therapeutic methods and pharmaceutical compositions are provided as well.

What is claimed is:  
     
       1. A method for treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       2. The method of  claim 1 , wherein the estrogen-dependent disorder is breast cancer. 
     
     
       3. The method of  claim 1 , wherein the estrogen-dependent disorder is uterine cancer. 
     
     
       4. A method for treating an individual with an non-estrogen dependent cancer, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       5. The method of  claim 4 , wherein the cancer is multiple drug-resistant. 
     
     
       6. A method for increasing bone mass in the body of a mammalian individual, comprising administering to the individual an effective bone mass increasing amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       7. A method for inhibiting bone loss in the body of a mammalian individual, comprising administering to the individual an effective bone loss inhibiting amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       8. A method for lowering serum cholesterol in the body of a mammalian individual, comprising administering to the individual an effective serum cholesterol lowering amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       9. A method for inhibiting a pulmonary hypertensive disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       10. A method for inhibiting skin atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       11. A method for inhibiting vaginal atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       12. A method for inhibiting an estrogen-dependent CNS disorder, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       13. A method for treating osteoporosis in the body of a mammalian individual, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       14. A method for inhibiting a CNS disorder in a postmenopausal human female, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R 29  and R 30  are not both hydrogen; and  
       L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.  
     
     
       15. A method for treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       16. The method of  claim 15 , wherein the estrogen-dependent disorder is breast cancer. 
     
     
       17. The method of  claim 15 , wherein the estrogen-dependent disorder is uterine cancer. 
     
     
       18. A method for treating an individual with an non-estrogen dependent cancer, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       19. The method of  claim 18 , wherein the cancer is multiple drug-resistant. 
     
     
       20. A method for increasing bone mass in the body of a mammalian individual, comprising administering to the individual an effective bone mass increasing amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       21. A method for inhibiting bone loss in the body of a mammalian individual, comprising administering to the individual an effective bone loss inhibiting amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       22. A method for lowering serum cholesterol in the body of a mammalian individual, comprising administering to the individual an effective serum cholesterol lowering amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       23. A method for inhibiting a pulmonary hypertensive disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       24. A method for inhibiting skin atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       25. A method for inhibiting vaginal atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       26. A method for inhibiting an estrogen-dependent CNS disorder, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       27. A method for treating osteoporosis in the body of a mammalian individual, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.  
     
     
       28. A method for inhibiting a CNS disorder in a postmenopausal human female, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety                    
       at the C-11 position of the estratriene nucleus, wherein: 
       j is an integer in the range of 0 to 5 inclusive;  
       p is an integer in the range of 0 to 6;  
       R 29  and R 30  are lower alkyl or are linked together to form a heterocycloalkyl ring; and  
       Q 1 , Q 2 , Q 3  and Q 4  are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.